tbuckley/cabot-search huggingface dataset:
Association of Driver Oncogene Variations With Outcomes in Patients With Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Consolidative Durvalumab
Authors: Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Carl M. Gay, Xiuning Le, Matthew S. Ning, Jeff Lewis, Vadeerat Rinsurongkawong, J. Jack Lee, Jack Roth, Stephen Swisher, Saumil Gandhi, Percy P. Lee, Don L. Gibbons, Ara A. Vaporciyan, John V. Heymach, Jianjun Zhang, Steven H. Lin
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non–small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear. <h3>Objectives</h3> To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen. <h3>Design, Setting, and Participants</h3> This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May 2020. Patients with recurrent disease or those receiving postoperative therapy were excluded. Outcomes were analyzed with Kaplan-Meier and multivariate regression analyses. <h3>Exposures</h3> Patients were grouped according to the presence of non–<i>KRAS</i>driver variations (<i>EGFR</i>exon 19 deletion,<i>EGFR</i>exon 20 insertion,<i>EGFR</i>exon 21 mutation [L858R],<i>ERBB2</i>exon 20 insertion,<i>EML4-ALK</i>fusion,<i>MET</i>exon 14 skipping,<i>NTRK2</i>fusion),<i>KRAS</i>driver variations, or no driver variations. <h3>Main Outcomes and Measures</h3> The primary outcomes were PFS, OS, and second progression-free survival (PFS2) times. <h3>Results</h3> The 104 patients had a median (IQR) age of 65.1 (9.8) years, with 55 females (53%) and 85 former or current smokers (88%). There were 43 patients (41%) with driver variations with a median PFS time of 8.4 months vs 40.1 months for patients without driver variations (hazard ratio [HR], 2.75; 95% CI, 1.64-4.62; log-rank<i>P</i> &lt; .001). Both patients with non–<i>KRAS</i>and<i>KRAS</i>driver variations had worse PFS. No difference in OS was found between patients with and without driver variations (log rank<i>P</i> = .24). Among the 63 patients who developed progressive disease, those with non–<i>KRAS</i>driver variations had a median PFS2 time of 13.7 months vs 4.4 months for all other patients (HR, 0.37; 95% CI, 0.21-0.64; log-rank<i>P</i> = .001). Rates of overall grade 2 toxic effects or higher did not differ by driver mutation status. <h3>Conclusions and Relevance</h3> In this cohort study, driver variations in patients with unresectable locally advanced NSCLC were associated with significantly shorter PFS time after definitive chemoradiation and consolidative durvalumab. These findings suggest the need to consider additional or alternative treatment options to the PACIFIC regimen for patients with driver variations.
Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms
Authors: V Biasci, L Santini, S Hussaini, C Ferrantini, R Coppini, LM Loew, S Luther, M Campione, C Poggesi, FS Pavone, E Cerbai, G Bub, L Sacconi
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ions channel recovery and intracellular Ca2+-cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose a novel approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination) but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsins-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We use an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role that cardiac alternans plays in spontaneous termination of ventricular tachycardias (VTs). We find that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.
DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS
Authors: Tyler A. Herek, Alyssa Bouska, Waseem Lone, Sunandini Sharma, Catalina Amador, Tayla B. Heavican, Yuping Li, Qi Wei, Dylan Jochum, Timothy C. Greiner, Lynette Smith, Stefano Pileri, Andrew L. Feldman, Andreas Rosenwald, German Ott, Soon Thye Lim, Choon Kiat Ong, Joo Song, Elaine S. Jaffe, Gang Greg Wang, Louis Staudt, Lisa M. Rimsza, Julie Vose, Francesco d’Amore, Dennis D. Weisenburger, Wing C. Chan, Javeed Iqbal
Journal: Blood (2022)
Identification of super-exhausted T cells: A novel population predictive of response to immunotherapy.
Authors: Florent Peyraud, Jean-Philippe Guegan, Christophe Rey, Sophie Cousin, Guilhem Roubaud, Mathilde Cabart, Maxime Brunet, Ezogelin Oflazoglu Gruyters, Ariel Savina, Sylvestre Le Moulec, Bérangère Dadone-Montaudon, Fabrice Barlesi, Benjamin Besse, Yohann Loriot, Aurelien Marabelle, Jean-Charles Soria, Jean-Yves Scoazec, François Le Loarer, Alban Bessede, Antoine Italiano
Journal: Journal of Clinical Oncology (2022)

2596 Background: Given that most of cancer patients treated with anti-PD1/PD-L1 immune checkpoint blockers (ICB) do not derive benefit, there is a crucial need to identify reliable predictive biomarker of response. Besides PD-1, several key immune checkpoints, such as CTLA4, LAG3, TIM3 and TIGIT, are associated with a T cell exhausted phenotype and play a crucial role in leading to cancer immune evasion. The impact of simultaneous expression by T cells of distinct inhibitory receptors on outcome of patients treated with ICB is still unknown. Methods: We analyzed the tissue samples, collected before ICB initiation, from patients with solid tumors and included in an institutional molecular profiling program (NCT02534649). We used multiplexed-immunohistofluorescence with the following panel CD3/PD1/TIM3/LAG3/TIGIT/CTLA4, and performed immune cell characterization using multispectral images analysis. We then investigated the correlation between coexpression of T cell-associated exhaustion markers, clinical response rate, progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards models. Results: Four hundred thirty five patients were included in the analysis (NSCLC: n=207, 47.6%; sarcoma: n=42, 9.7%; urothelial: n=30, 6.9%; others: n=156, 35.9%). Digital pathology analysis allowed us to identify a population of “super-exhausted” T cells characterized by the co-expression of PD1, LAG3, TIGIT and TIM3 which was enriched in 125 cases (28.7%), and was significantly associated with better PFS (HR 1.60, CI95 1.26-2.04, p&lt;0.001) and OS (HR 1.42, CI95 1.07-1.89, p=0.016) in the whole cohort. Patients with super-exhausted high tumors had higher objective response rate (38.4%) compared to super-exhausted low tumors (19.7%, p&lt;0.001). The presence of super-exhausted T cells was significantly higher in responders (10%) versus non responders (4%, p&lt;0.001). Correlation with better outcome was observed whatever the subgroup considered (NSCLC vs other tumors, CD8 T cells density and presence of tertiary lymphoid structure [TLS]). In multivariate analysis (n=372, 85.5%), increased tumor infiltration by super-exhausted T cells (&gt;1 %) was significantly associated with better PFS (HR 0.61, CI95 0.46-0.81, p&lt;0.001, Table) and OS (HR 0.68, CI95 0.48-0.97, p=0.033, Table). Conclusions: The presence of super-exhausted T cells may represent a new predictive biomarker of response to ICB and pave the way for the development of effective ICB combinations. Data from an independent validation cohort will be presented at the meeting. [Table: see text]
Phase 1/2 study of devimistat in combination with hydroxychloroquine (HCQ) in patients with relapsed or refractory (R/R) clear cell sarcoma (CCS).
Authors: Mark Agulnik, Elizabeth J. Davis, Catherine M. Albert, Lara E. Davis, Timothy S. Pardee, Rashmi Chugh, Matteo M. Trucco
Journal: Journal of Clinical Oncology (2022)

TPS11595 Background: CCS of the soft tissues is a rare and aggressive subtype of sarcoma that often starts in the tendons of the arms or legs. It is molecularly characterized by t(12;22)(q13;q12) translocation, resulting in EWSR1-ATF1 or EWSR1-CREB1 gene fusion. Despite reports of occasional responses to systemic therapies, currently available therapies have shown limited efficacy in advanced CCS. Therefore, there is a significant unmet medical need for more active agents in CCS. Devimistat is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle preferentially within the mitochondria of cancer cells. Devimistat induces autophagy in cancer cells. In a metastatic mouse model of CCS, treatment with devimistat in combination with chloroquine significantly suppressed tumor growth (Egawa et al, 2018). Based on this data, we hypothesized that inhibition of autophagy with HCQ may sensitize cancer cells to devimistat with increased efficacy and acceptable toxicity. Given its expected synergy, we have initiated a single-arm phase I/II prospective, multicenter, open-label, non-randomized study to evaluate maximally tolerated dose (MTD), safety, and efficacy of devimistat in combination with HCQ in patients with R/R CCS. Methods: In the phase 1 portion of the study, patients with R/R CCS and other fusion-positive R/R sarcomas will be enrolled and a standard 3+3 design will be followed to evaluate toxicity, MTD, and recommended phase 2 dose. There will be two patient groups based on weight, and dose escalation will be conducted separately for each group. Starting dose of HCQ will be 5mg/kg PO BID for patients &lt; 45 kg and 200 mg PO BID for patients ≥45 kg on days 1 through 5 of every 28 days. The first dose of HCQ each day will be followed 2 hours later by 1,000 mg/m 2 devimistat (for patients &lt; 45 kg) and 2,000 mg/m 2 of devimistat (for patients ≥ 45 kg) administered over 2 hours. A maximum of 36 patients will be enrolled for the phase I portion, 18 for each patient group. In the phase 2 portion of the study, only relapsed or refractory CCS patients will be enrolled, and the response rate will be determined using RECIST 1.1. In phase 2, pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, overall survival, safety, and patient-reported outcomes will also be assessed. This portion of the study will utilize Simon’s admissible two-stage design with 29 patients. This study started enrolling participants in November 2021 and has dosed six patients to date. The first two dose-escalation cohorts for patients ≥45 kg have been completed without DLT and the third dose level will be opening shortly. Clinical trial information: NCT04593758.
A novel translational stratification system for electrophysiological characterization: evaluating arrhythmia complexity from the lab to the clinic
Authors: AM Sanchez De La Nava, L Gomez-Cid, ME Fernandez-Santos, A Arenal, F Atienza, F Fernandez-Aviles
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III CIBERCV Introduction Cardiac arrhythmias can originate as a consequence of the proarrhythmic effects of some therapeutical regenerative products. In vitro studies have demonstrated different levels of electrophysiological complexity but these models usually lack of direct translation into the clinical practice. Objective To develop an arrhythmia complexity evaluation method that enables to characterize electrophysiological complexity in translational scenarios. Methodology: To build a new evaluation method, frequency and rotor biomarkers from in vitro cell cultures presenting fibrillatory activity (N=15) were evaluated using optical mapping recordings (Rhod-2AM Ca2+ transient dye, 30-minute incubation, excited with green light). The patterns observed at in vitro level were analyzed and characterized by means of frequency and rotor biomarkers. Next, we performed a forward translational study to evaluate these electrophysiological biomarkers at a clinical level. In 206 patients with atrial fibrillation (AF) with non-invasive body surface recordings using the Acorys system from Corify (67 electrodes, 4 second segments) (STRATIFY-AF study) were evaluated to analyze the same frequency and rotor biomarkers previously explored in vitro. Moreover, we build a complexity score that described from 0 to 1 the complexity at electrophysiological level, where 0 corresponded to simple scenarios and 1 to complex arrhythmic patterns. Patients were followed for 12 months to evaluate long term evolution. Results Complexity evaluation method identified the highest dominant frequency, median frequency and rotor time as the most important predictors for arrhythmia complexity definition. In vitro cultures results showed that samples presenting higher dominant frequency were also associated with small dominant frequency area extension and lower rotor time maintenance, i.e., with a high value of the complexity biomarker (Figure 1B). At clinical level, patients with high values of the complexity score were identified with Persistent AF patients showing complex patterns in whom AF recurred after ablation at 12 months (Figure 1D). Conclusions We developed a translational approach that enables to characterize arrhythmia complexity in different frameworks, which is crucial to evaluate potential undesirable effects of therapeutical regenerative products during the complete development and validation of the product.
Global variation in quality of transurethral resection of bladder surgery, results from the RESECT study
Authors: K.M. Gallagher, N.R. Bhatt, K.D. Clement, E.F. Zimmermann, S. Khadhouri, M. Kulkarni, T. Anbarasan, V.W-S. Chan, A. Light, C.M. Lam, A. Asif, F.G. Gaba, S.H. Rossi, C. Gao, A. Nathan, T.S. O'Brien, S. Maclennan, N. Matthew, P. Mariappan, V. Kasivisvanathan
Journal: European Urology (2022)
Surgical subtype and survival in stage I chondrosarcoma: A National Cancer Database (NCDB) analysis.
Authors: Michael Burdyny, Vincent Eaton, Connor Tupper, Ashton Legenza, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

e23502 Background: Chondrosarcoma is one of the most common primary malignancies of bone and commonly presents in adults in its early stages. Standard of care for chondrosarcoma is currently surgical intervention, with radiation therapy for cases where complete resection is not possible; chemotherapy is minimally effective. To the authors’ knowledge, there is little literature regarding different surgical subtypes for chondrosarcoma patients. To address this, the aim of our study is to assess survival outcomes in stage I chondrosarcoma patients based off of different surgical subtypes. Methods: Using the NCDB, patients diagnosed with stage I chondrosarcoma between 2004-2018 were identified using ICD-O-3 histology codes 9220 and 9221. The cohort was analyzed to determine if they received any form of surgical intervention and which surgical subtype they received. We then performed univariate analysis to assess patient length of survival for each surgical subtype. Data was analyzed using SPSS and statistical significance was set at α = 0.05. Results: A total of 5186 patients were included that had survival data, of which 4752 received surgical intervention. The mean survival time was 152.1 months for all patients. Surgical patients survived an average of 156.6 months while nonsurgical patients survived just 97.7 months (p &lt; .0001). Analysis of surgical types revealed local destruction and local excision had the longest mean survival but were not different from each other (p &gt; .05). Local excision had significantly longer survival than radical excision with limb sparing (p &lt; .05). Local, partial, and radical excision all resulted in longer survival than limb and major amputations (all p &lt; .01). Patients who underwent major amputation survived longer than limb amputation, but this difference was not significant (p &gt; .05). Conclusions: This study found that receipt of surgery is associated with improved survival in chondrosarcoma patients. Receiving different surgical interventions may influence survival as patients receiving local excision survived longer than radical excision with limb sparing. Future studies should investigate additional variables that may influence receipt of surgery such as patient demographics, insurance status, and treatment facility type.[Table: see text]
Biodegradable nanoparticles inhibit tumor growth by altering tumor-associated macrophages and cancer-associated fibroblasts.
Authors: Tushar Murthy, Joseph Podojil, Taekyoung Kwak, Prashanthi Vonteddu, Adam Elhofy, Michael Boyne, John Puisis, Filippo Veglia, Surya Singh, Farokh Dotiwala, Luis Montaner, Dmitry Gabrilovich, Laxminarsimha Donthireddy, Rukiye-Nazan Eraslan
Journal: Journal of Clinical Oncology (2022)

e14553 Background: The tumor microenvironment (TME) plays a crucial role in tumor growth and progression and has a significant influence on response to therapy. The TME consists of myeloid-derived cells, stroma (e.g. fibroblasts and extracellular matrix (ECM)), and the vasculature that together support tumor growth and progression. Studies in animal models and in humans show that myeloid- derived cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) engage in activities that support tumor growth and progression. These cells also promote immune suppression in the TME that blunts the efficacy of the anti-cancer drugs and immune-targeted therapies such as immune checkpoint inhibitors. In addition to MDSCs, cancer-associated fibroblasts (CAFs) in the TME support tumor progression via production of pro-tumor and pro-angiogenic growth-factors, remodeling of the ECM via production of proteases, and suppression of anti-tumor immune function. CAF abundance in the TME is a negative prognostic factor for several solid tumors and is associated with negative outcomes and poor response to immune-targeted therapies like immune checkpoint inhibitors. ONP-302 nanoparticles fabricated from biodegradable poly (lactic-co-glycolic acid)(PLGA) polymer have been previously described in the literature for the treatment of acute inflammatory conditions via immuno-modulatory effects on myeloid derived cells. Here, we evaluated the efficacy of ONP-302 nanoparticles at inhibiting tumor growth via targeted inhibition of myeloid-derived cells and reshaping of the TME. Methods: ONP-302 anti-tumor efficacy was evaluated in syngeneic mouse tumor models using both immunocompetent and immunodeficient mice. We examined the effect of ONP-302 treatment tumor growth kinetics and effects on the major cellular constituents of the TME such as myeloid-derived cells and CAFs. Results: Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. We found ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Conclusions: Our data indicate that the slowing of tumor growth after ONP-302 treatment is due to disruptions in known signaling pathways involving TAMs and CAFs, pathways typically supporting tumor growth. These data taken in concert indicate the activity of ONP-302 is pleotropic and affects multiple pathways.
MEDB-56. POx NPs mediated delivery of (TLR7/8) agonist resiquimod improves treatment outcomes in SHH medulloblastoma by targeting tumor associated macrophages
Authors: Duhyeong Hwang, Coral del Mar Alicea, Chaemin Lim, Christopher Park, Timothy Gershon, Marina Sokolsky-Papkov
Journal: Neuro-Oncology (2022)

Abstract Cancer immunotherapy, the utilization of the patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. Recent clinical data has demonstrated immunotherapy to be effective in a wide range of cancers, including lung, bladder, renal cell, colorectal, gastro-esophageal, and head and neck cancers5-11. However, clinical reports of immune-based treatments for medulloblastomas are scarce and preliminary. Therefore, there is a need in developing strategies to improve medulloblastoma immunotherapy. Our recent studies have confirmed that SHH medulloblastomas are enriched in Tumor Associated Macrophages (TAMs) and unlike other tumors, TAMs are associated with positive outcomes and play a positive role by impairing tumor growth. Overall, analysis of TME in medulloblastomas reveals TAMs as a potential therapeutic target. Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR7/8) that modulates innate immune cells. We have loaded resiquimod into ultra-high-capacity polyoxazoline (POx) block copolymers forming small, homogeneous nanoparticles (POx-resiquimod). Our recent study shows that loading into POx nanoparticles improves drug delivery to tumors and treatment with 3 injections of POx-res as the single-agent treatment results in a profound anti-tumor effect G-Smo mice while treatment with free drug shows no therapeutic benefit. Our data also shows that that the tumors of G-Smo mice are enriched with the mixed populations of anti-inflammatory and pro-inflammatory macrophages and the treatment with POx-resiquimod have enhanced infiltration of macrophages into the tumors, enhanced the repolarization of macrophages to M1 subtype and decreased tumor cells viability. These studies show for the first time that targeting the medulloblastoma TME with POx-resiquimod can produce a significant anti-tumor effect. Furthermore, combination of POx-resiquimod with radiation resulted in long term survivals, showing potential therapeutic combination. The expression of TLR7/8 on TAMs in patient-derived medulloblastoma samples suggests that resiquimod may produce similar anti-medulloblastoma effects in humans.
Patients’ preferences, willingness-to-pay and cost of cystoscopy procedures: Results from a large survey-based study in the United Kingdom
Authors: O.D. Bæk, D. Batura, A.W. Thorpe, F.M. Maqboul, D.K. Rindorf, E.D.L. Dehlholm-Lambertsen, J.V. Vangsgaard, J.P. Patterson
Journal: European Urology (2022)